Metal complexes of isoniazid



United A States Patent Office 2,194,019 P atel'llfed May 28, 1957 METAL COMPLEXES OF ISONIAZID Siegfried Petersen, Leverkusen-Schlebusch, Otto Bayer,

Leverkusen-Bayerwerk, Hans -Albert'Olfe, Leverkusen Wiesdorf, and Gerhard Domagk, Wuppertal-Elberfeld, Germany, assignors to Schenley Industries, Inc., New

York, N. Y., a corporation of Delaware No Drawing. Application December 1, 1953, Serial No. 395,613

Claims priority, application Germany December 10, 1952 6 Claims. (Cl. 260-270 Our present invention relates to heterocyclic carboxylic acid hydrazide metal complexes produced by the interaction of compounds, particularly salts, of metals of the second to eighth groups of the periodic system with heterocyclic carboxylic acid hydrazides such as isonicotinic acid hydrazide and pyromucicacid hydrazide and to procedure for preparing such metal complexes.

It is known that isonicotinic acid hydrazide is capable of forming complex compounds withbivalent copper ions, which complex compounds have been alleged to show tuberculostatic activity. It has been found, however, that the alleged tuberculostatic activity is very v new metal complexes.

slight and that the compatibility of such complex compounds is greatly restricted because of the relatively high toxicity of copper. While it has been previouslyknown that copper has the capacity of forming complex compounds when employed in a form making copper ions available, the previous work has been shown to be specific for copper only. i

It was, therefore, surprising and unpredictable that isonicotinic acid hydrazide and'hydrazides of other heterocyclic carboxylic acids having tuberculostatic activity possess a marked capacity for forming metal complexes with organic and inorganic metal compounds to permit the production of metal complexes with various metals of groups 2-8 of'the periodic system. We have found that among these metal complexes there are a number of new heterocyclic carboxylic acid hydrazide derivatives which are distinguished by excellent chemotherapeutic activity together with good compatibility. In this respect we have found that many of the metal complexes to be hereinafter described are markedly superior to isonicotinic acid hydrazide, as such, and to its copper complex compound. As will be hereinafter also set forth, certain of our new derivatives are of value in animal therapy.

According to our invention, heterocyclic carboxylic acids are employed as the starting material. Examples of heterocyclic carboxylic acids which are useful inour invention are isonicotinic acid, nicotinic acid, pyromucie acid, y-pyridine carboxylic acids, derivatives of 'y-pyridine carboxylic acids substituted in the nucleus by alkyl radicals, pyridyl acetic acids, pyridyl acrylic acids, pyridyl crotonic acids and other pyridyl alkanoic acids, quinoline carboxylic acids and pyrimidine carboxylic acids. These acids are converted into their hydrazides in known manner by reacting their esters, chlorides or anhydrides with hydrazine or with compounds yielding hydrazine.

We have found that various organic and inorganic metal compounds of complex-forming metals of groups 2-8 of the periodic system can be successfully utilized but we preferably employ inorganic metal salts as these 2 to the use of ferric chloride, which may give rise to some difficulties when used under conditions similar to those of ferrous sulfate, but it is to be understood, nevertheless, that our invention is not restricted to the use of metal salts in which the metal is in its lower valency form. Metal sulfates have been found to be particularly'advantageous since they frequently yield only slightly soluble complexes with the heterocyclic carboxylic acid hydrazides. We may also employ metal salts of hydrohalic acids, nitric acid, acetic acid and other inorganic and organic acids. .In addition, complex compounds which add further ligands or exchange ligands may be employed under appropriate conditions. Metal compounds may, furthermore, be employed which do not have a salt-like character, such as the metal alcoholates and the reaction products of metals with acetyl acetone, and such have been found to be useful in and applicable to our invention.

The selected components are reacted in an aqueous medium or in organic solvents. Methyl alcohol has been found to be particularly useful and desirable as an organic solvent but other organic solvents may also be successfully employed, such as ethyl alcohol, acetone, tetrahydrofurane, formamide, dimethylformamide and pyridine. Whenthe reaction is carried out in the presence of ligands capable of forming complexes, such as ammonia, amines and cyanogen ions, these become incorporated into the Our new metal complexes are generally characterized by being well crystallized compounds showing valuable therapeutic properties and in the therapeutic application of our new preparations only part of the hydrazide of the heterocyclic carboxylic acid may be converted into the metal complex or the metal complexes may be used in admixture with on another or admixed with the heterocyclic carboxylic acid hydrazide and these mixtures employed therapeutically.

The invention is illustrated by the following examples without limiting it thereto:

I Example 1 An aqueous solution of 56.2 grams of crystallized ferroussulfate of the formula FSO4'7H2O in 100 cc. of water is addedto a solution of 13.7 grams of isonicotinic acid hydrazide in 100 cc. of water at 45 C. A light brown solution is formed from which light brown crystals separate after a short time. The crystals are suction filtered after two hours and washed with water. 32 grams of the brown iron complex are obtained, which slowly become dark brown upon heating to above 200 C. The filtrate of the reaction mixture'still contains abundant quantities of ferrous ions. It is, therefore, possible 'to use only half the quantity of iron sulfate; by'doing so, however, a someare particularly effective. In using metals'havingmore lutions a voluminous brownish-yellow precipitate forms formation of our new metal complexes and is preferable what lesser yield (30 grams) is obtained. An excessof ferrous sulfate is thus preferred." The product may be represented by the formula:

Ooo-Ninrrm rsoi-snto I Example 2' 27.4 grams of isonicotinic acid hydrazide are dissolved in 250 cc. of boiling methanol. A solution of 30 grams of ferrous sulfate. (FeSO417H2O),which has been prepared at low temperature, is added to the hydrazide solution. It is to be noted that the ferrous sulfate solution must be prepared carefully and rapidly since, otherwise, precipitation occurs very soon. Upon combining the soinstantly. The combined solutions are boiled on the water bath for 10 minutes and the reaction product is suction filtered while hot and washed with a hot methanol solution. After drying at room temperature 34 grams of a light brown product are obtained, which is insoluble in water, but slowly attains a red-brown coloration by treating it with water, whereby the complex presumably represented by the following formula is obtained:

Example 3 A solution of 55 grams of manganous chloride in 100 cc. of water heated to 60 C. is introduced into a solution .of 41.1 grams of isonicotinic acid hydrazide in 50 cc. of water also heated to 60 C. The faintly pink coloration of this solution immediately turns light brownish. On cooling almost white needle-shaped crystals slowly precipitate, which are suction filtered after two hours. Since these crystals are readily water soluble they are washed with very little water and alcohol. The yield is 34 grams. The substance does not melt at temperatures up to 280 C. The complex may be represented by the formula:

Example 4 A solution of 12.5 grams of magnesium sulfate (MgSO4-7H2O) in 200 cc. of methanol, which has been prepared carefully in the cold, is added to a solution of 27.4 grams of isonicotinic acid hydrazide in 200 cc. of boiling methanol as described in Example 2. After a short time the desired magnesium complex crystallizes well in the hot solvent; the compound, which is isolated while hot and washed with hot methanol, is snow-white, can be dried at 70 C. and does not melt at temperatures up to 200 C. Upon grinding, the compound is strongly charged with static electricity. The yield is 19.2 grams. The complex may be represented by the formula:

Example 5 The 12.5 grams of magnesium sulfate of Example 4 were replaced by 14 grams of crystallized nickel sulfate (NlSO4'7H20), which had been dissolved in 200 cc. of hot methanol. Following the procedure of Example 4, a weakly bluish nickel complex is obtained in a yield of 21.5 grams. The product may be represented by the formula:

Example 6 82 grams of isonicotinic acid hydrazide are dissolved in 250 cc. of water at 50 C. 90 cc. of 6.5/n-sulfuric acid are added and 170 grams of cobalt sulfate (bivalent cobalt) dissolved in 250 cc. of water at 50 C. are introduced into the mixture. After minutes pink colored crystals precipitate from the red-brown clearsolution; they propagate rapidly and finally cause solidification of the mixture as a pink colored paste. The paste is suction filtered after two hours and the slightly water-soluble compound thoroughly washed with water. Finally, the compound is covered with alcohol and dried at 50 C.

94 grams of a compound containing 15.2 percent of cobalt and having the atomic ratio cobaltznitrogen'zsulfur=1:3:1 are obtained having superior tuberculostatic activity. The product may be represented by the for- Example 7 31.5 grams of pyromucic acid hydrazide are dissolved in 100 cc. of water and 250 cc. of l/n-sulfuric acid. 71

grams of crystallized cobalt sulfate in 200 cc. of water are added. No precipitation occurs in the dirty red solution, not even on standing over night. The solution is, therefore, evaporated under vacuum, whereupon, finally, faintly pink colored crystals precipitate. The crystals are separated from the mother liquor by filtering and .Washed with very little water since the compound is readily water-soluble. Finally, the compound is washed with tetrahydrofurane and dried. The cobalt complex is obtained in the form of a pink colored powder. The product may be represented by the formula:

Example 8 13.7 grams of isonicotinic acid hydrazide are dissolved in cc. of cold water. 25 grams of cobaltous chloride dissolved in 50 cc. of water are added thereto. Rose-colored crystals of the desired cobalt complex precipitate over night from the clear red-brown solution. The crystals, which are relatively slightly soluble in water, are suction filtered and washed with water and alcohol. The product may be represented by the for- Example 9 A solution of 13.6 grams of zinc chloride is slowly introduced into a boiling solution of 27.4 grams of iso nicotinic acid hydrazide in 300 cc. of ethyl alcohol. A precipitate forms immediately. After refluxing for one hour a heavy yellowish-white powder is obtained in a yield of 28 grams. The powder can be dried at elevated temperatures and is very readily soluble in water. The complex may be represented by the formula:

In analogous manner a solution of zinc chloride can be reacted with pyromucic acid hydrazide in alcohol. A white zinc complex is thus obtained.

Example 10 A lukewarm solution of 22.8 grams of antimony trichloride in methanol is slowly introduced drop-wise into a solution of 27.4 grams of isonicotinic acid hydrazide in 300 cc. of boiling methanol. A yellow coloration is observed first; after that turbidity occurs. Light orange, heavy crystals slowly precipitate and are suction filtered after one hours boiling and washed with hot methanol. 29 grams of the antimony complex are obtained, which slowly decompose upon heating above 200 C. passing through a semifluid stage finally to solidify again. The complex may be represented by the formula:

It will, therefore, be appreciated and understood that our new metal complexes may be prepared from a suitable heterocyclic carboxylic acid hydrazide and a metal compound, preferably a metal salt, of a complex-forming metal selected from the second to eighth groups of the periodic system. These new complexes have excellent therapeutic activity especially as tuburculostatic agents, good compatibility and satisfactory non-toxicity. They may be administered in the same manner as isonicotinic acid hydrazide.

Our new metal complexes of heterocyclic carboxylic acid hydrazides may be represented by the general formula RCONH-NH2 MeX solvent wherein R is the residue of the heterocyclic carboxylic acid, Me is the metal, X is the anion or anionic portion of the metal compound employed and solvent is water or alcohol of crystallization. For example, when isonicotinic acid hydrazide and cobalt sulfate (C0SO4-7H2O) are employed, R is CsHtN, Me is Co, X is'SOr and solvent is 3H2O. In such case, therefore, as set forth in Example 6, the new metal complex responds to the formula- Depending upon the particular metal, the particular inorganic or organic compound thereof and the solvent employed, the general formula varies as to the proportions of Me and X in the MeX component with each other and with relation to the heterocyclic carboxylic acid hydrazide and also varies as to the presence of water or alcohol of crystallization. In general, it is preferred to utilize metal compounds in which the metal is in a lower stage of oxidation since this avoids destruction of free heterocyclic carboxylic acid hydrazide and simplifies the preparation of the new metal complexes.

Thus, the new metal complexes, as exemplified by isonicotinic acid hydrazide metal complexes, may be summarized as follows:

The molecular ratio of hydrazide to metal atom varies from approximately 1:025 in the case of magnesium (Example 4) or nickel (Example 5) to 112.0 in the case I tuburculostatic activity coupled with good compatibility and non-toxicity and are suitable for employment in both human and animal therapy.

The scope of the invention is defined by the appended claims We claim:

1. A metal complex of isonicotinic acid hydrazide having the formula:

in which MeX is a metal compound wherein Me is a metal. selected from the group consisting of iron, cobalt,

manganese, magnesium, antimony, nickel and zinc, X is the anion of the metal compound MeX and solvent represents at least 1 mol'of solvent of crystallization selected from. the group consisting of water, methanol and ethanol.

2. The complex having the formula '3. The complex having the formula 4. The complex having the formula 5. The complex having the fo rmula 6. The complex having the formula References Cited in the file of this patent J. Pharm. Soc., Japan, vol. 73: 818-20 (1953) as abstracted in Chem. Abstrx, vol. 47, col. 12636 (Nov. 10, 1953).

Experentia (Ehrlenmeyer), vol. 8, Aug. 15, 1952, pp. 298-299. 

1. A METAL COMPLEX OF ISONICOTINIC ACID HYDRAZIDE HAVING THE FORMULA: 